Inheritance of a germline mutation in the BRCA1 or BRCA2 (BRCA1/2) genes is associated with an increased risk of developing breast and ovarian cancer. However, there is also substantial variability in the penetrance of breast cancer in BRCA1/2 mutation carriers. These observations imply that germline mutations in BRCA1/2 may be necessary to explain the Mendelian pattern of cancer in some families, but may not be sufficient to completely describe the inter-individual variability in the age-specific risk of cancer. There is substantial evidence that BRCA1/2-associated breast carcinogenesis involves the recognition and repair of DNA damage to maintain genomic integrity. The goal of this proposal is to identify genotypes involved in DNA damage recognition and repair pathways that influence BRCA 1/2-associated breast cancer risk. This proposal will be facilitated by the resources of a multidisciplinary collaborative group that has collected data on over 2,000 BRCA1/2 mutation carriers. This existing data resource provides a unique opportunity to accomplish the following specific aims. We hypothesize that in the presence of a mutated BRCA1 or BRCA2 gene, additional inherited variants that confer additional impairment to DNA damage recognition or repair will alter the penetrance of breast cancer. The goal of this proposal is to identify genotypes involved in DNA damage recognition and repair pathways that influence BRCA1/2-associated cancer risk. This proposal will be facilitated by the resources of a multidisciplinary collaborative group that has collected data on over 2,000 BRCA1/2 mutation carriers. We propose to increase the size of this cohort during the funding period and generate and epidemiologically appropriate nested study sample to accomplish the following specific aims: Specific Aim 1: To use a case-only study of BRCA1/2 mutation carriers to evaluate whether candidate genes alter the characteristics of breast tumors; Specific Aim 2: To use a nested case-control study to evaluate whether candidate genes are associated with altered breast cancer risk; Specific Aim 3: To use a nested case-control study to evaluate whether candidate genes predict cancer site (breast vs. ovarian). Knowledge about cancer risk modifiers may improve our risk assessment ability, identify relevant pathways of BRCA1/2-mediated carcinogenesis, and identify exposures that can be used to develop appropriate cancer prevention strategies. Our substantial multidisciplinary experience will therefore allow us to readily translate basic science and epidemiological data to clinically relevant information.